EP2903607B1 - A combination of adrenalin with an antidepressant for use in the treatment of shocks - Google Patents

A combination of adrenalin with an antidepressant for use in the treatment of shocks Download PDF

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Publication number
EP2903607B1
EP2903607B1 EP13771500.9A EP13771500A EP2903607B1 EP 2903607 B1 EP2903607 B1 EP 2903607B1 EP 13771500 A EP13771500 A EP 13771500A EP 2903607 B1 EP2903607 B1 EP 2903607B1
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EP
European Patent Office
Prior art keywords
adrenalin
antidepressant
pharmaceutical composition
solution
shock
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP13771500.9A
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German (de)
English (en)
French (fr)
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EP2903607A1 (en
Inventor
Jean-Charles Schwartz
Xavier Ligneau
Laurent François Gérard LANDAIS
David Perrin
Jeanne-Marie Lecomte
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Bioprojet SC
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Bioprojet SC
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Publication date
Priority to SM20170502T priority Critical patent/SMT201700502T1/it
Application filed by Bioprojet SC filed Critical Bioprojet SC
Priority to RS20170973A priority patent/RS56392B1/sr
Priority to NO13771500A priority patent/NO2903607T3/no
Priority to HRP20171442TT priority patent/HRP20171442T1/hr
Priority to EP13771500.9A priority patent/EP2903607B1/en
Priority to SI201330817T priority patent/SI2903607T1/sl
Priority to PL13771500T priority patent/PL2903607T3/pl
Publication of EP2903607A1 publication Critical patent/EP2903607A1/en
Application granted granted Critical
Publication of EP2903607B1 publication Critical patent/EP2903607B1/en
Priority to CY20171101135T priority patent/CY1119514T1/el
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • the present invention concerns a novel combination of adrenalin with an antidepressant for use in the treatment of shocks.
  • Circulatory shocks are life-threatening medical emergencies wherein the organs and tissues of the body are not receiving an adequate flow of blood and thus an adequate level of oxygen.
  • shocks There are three major types of shocks: cardiogenic, hypovolemic, and distributive shocks.
  • distributive shocks the anaphylactic shock and septic shock can be cited.
  • tachycardia Among the symptoms of shocks, it can be cited tachycardia, hypotension and signs of poor end-organ perfusion such as low urine output, confusion or weakness.
  • Anaphylaxis is a severe allergic reaction of rapid onset affecting many body systems and may cause death. It is due to the release of inflammatory mediators and cytokines from mast cells and basophils, typically due to an immunologic reaction but also, sometimes, non-immunologic mechanisms.
  • immunoglobulin E binds to an antigen.
  • Antigen-bound IgE then activates Fc ⁇ RI receptors (Fc epsilon RI receptors) on mast cells and basophils. This leads to release of inflammatory mediators such as histamine. These mediators subsequently increase the contraction of bronchial smooth muscles, trigger vasodilation, increase the leakage of fluid from blood vessels, and cause heart muscle depression.
  • Non-immunologic mechanisms involve substances that directly cause the degranulation of mast cells and basophils. These include agents such as contrast media, penicillins, opioids, temperature (hot or cold), and vibration.
  • adrenalin also called epinephrine or adrenaline
  • an injection of adrenalin within minutes of the onset of symptoms can be lifesaving ( Kemp SF et al. Allergy, 2008, 63, 1061-1 070 ); Muck A E et al., Annals of Emergency Medicine, 2010, 56 (3), 270-274 ).
  • Administration of adrenalin will increase vascular tone, myocardial contractility, and cardiac output in most cases.
  • Adrenalin is a well-known emergency treatment of circulatory shocks such as anaphylactic shock, cardiac arrest, and cardiovascular distress associated with anaphylactic shock, hemorragic shock, traumatic shock, infectious shock and secondary shock due to cardiac surgery.
  • the inventors have hypothesized that the diffusion of adrenalin in general circulation could be improved by the inhibition of the alpha-1 adrenergic receptor and/or by the inhibition of adrenalin capture by the noradrenalin/monoamine transporters.
  • the present inventors discovered that the combination of adrenalin with an antidepressant improves the diffusion of adrenalin into the general circulation, leading to a rapid and sustained plasma level. Also, the combination of adrenalin with an antidepressant accelerates the diffusion of adrenalin into general circulation, and/or blocks the main deleterious actions of released histamine.
  • adrenalin preferably administered together via intramuscular or subcutaneous route potentiates the action of adrenalin, thus involving a synergy between the two active ingredients.
  • Such effects are of great interest as they can be life-saving.
  • the invention therefore allows the combination of a ready-to-use treatment of shocks with an improved bioavailability in the first ten minutes following the intramuscular or subcutaneous injection of the combination adrenalin-antidepressant.
  • the combination according to the invention is thus of great interest in shocks for which the treatment comprises the quick administration of adrenalin as it improves the bioavailability of adrenaline, and can thus be life-saving.
  • Ki is meant the dissociation constant obtained by inhibiting the binding of a ligand or the inhibition constant obtained by inhibiting noradrenalin/adrenalin uptake.
  • the antidepressant can be chosen among the following classes:
  • the antidepressant is chosen among the tricyclic antidepressants (TCAs) or one of their pharmaceutically acceptable salts.
  • TCAs include:
  • the salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like, as well as salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, fumaric, methanesulfonic, and toluenesulfonic acid and the like.
  • the preferred pharmaceutically acceptable salts for the antidepressant are chosen among chlorhydrate, mesilate, maleate and fumarate.
  • the preferred pharmaceutically acceptable salts for adrenalin are chlorhydrate and tartrate.
  • the solution of the invention further comprises one or more pharmaceutically acceptable excipient(s) such as preservative agents, buffers, substance to make the solution isotonic with blood such as sodium chloride, solvents, stabilizers, or antimicrobial preservatives. It can be cited: sodium, hydrochloric acid or water for injection.
  • the excipients used are well-known to the skilled person. They should not adversely affect the stability, bioavailability, safety, or efficacy of the active ingredients, or cause toxicity or undue local irritation when the solution is to be administered by injection.
  • the solution of the invention further comprises at least one preservative agent.
  • the preservative agents are chosen among sodium metabisulfite, sodium bisulfite, ascorbic acid and/or their mixture.
  • the preservative agent is sodium metabisulfite.
  • adrenalin in the solution of the invention, is at a concentration comprised between 0.05 mg/ml and 1.0 mg/ml. In a particular embodiment, adrenalin is at a concentration between 0.15 mg/ml and 1.0 mg/ml. In another embodiment, adrenalin is at a concentration between 0.6 mg/ml and 1.0 mg/ml in formulations suitable for adults. In another embodiment, adrenalin is at a concentration between 0.1 mg/ml and 0.6 mg/ml in formulations suitable for children.
  • the invention also relates to a pharmaceutical composition comprising the solution as defined above.
  • the invention relates to a pharmaceutical composition comprising the solution as defined above, wherein the solution is suitable for injection.
  • An injection is an instrumental method used to introduce into the body a liquid pharmaceutical composition by parenteral administration.
  • injection is preferably meant a method of administration which can be intramuscular, subcutaneous or a transcutaneous penetration.
  • transcutaneous penetration is to be understood an injection by local pressure using devices without skin perforation by needle.
  • the pharmaceutical composition of the invention is suitable for intramuscular injection and/or subcutaneaous injection.
  • the pharmaceutical composition as defined above is administered by intramuscular injection.
  • the injection of the above defined pharmaceutical composition is not an intravenous injection.
  • the pharmaceutical composition of the invention is in a unit dosage form in which the injected volume is comprised between 0.1 ml and 0.5 ml. More preferably, the injected volume is of 0.3 ml.
  • the invention also relates to the pharmaceutical composition as defined above, for use in the treatment of shocks.
  • the invention also relates to the use of a solution as defined above for the preparation of a pharmaceutical composition to treat shocks.
  • the invention also relates to the solution as defined above for its use in the treatment of shocks.
  • the shock is chosen from the group consisting of: anaphylactic shock, cardiac arrest, and cardiovascular distress associated with anaphylactic shock, hemorragic shock, traumatic shock, infectious shock and secondary shock due to cardiac surgery.
  • the shock is the anaphylactic shock.
  • treatment it may be understood the treatment of the causes of the shock and/or the treatment of its symptoms, more particularly the treatment of its symptoms.
  • the auto-injection device comprises two containers wherein one container is prefilled with an aqueous solution of adrenalin, the other one container is prefilled with an aqueous solution of an antidepressant and wherein the pharmaceutical composition of the invention is formed by mixing the two solutions within the device.
  • aqueous solutions may be the commercially available solutions for injection comprising adrenalin on one hand and the antidepressant on the other hand and/or may exhibit similar concentrations, dosage unit forms, excipients as the solution of the invention disclosed above.
  • the auto-injection device as defined above comprises at least one prefilled container which is (are) suitable for injection of a volume of the pharmaceutical composition as defined above comprised between 0.1 ml and 0.5 ml.
  • the injected volume of the pharmaceutical composition of the invention is of 0.3 ml.
  • an aqueous solution of adrenalin and another aqueous solution of antidepressant may also be separate, provided they are administered at the same time, and at the same point of injection.
  • a point of injection is understood the area of action of the antidepressant which is the area where the antidepressant blocks totally or partially the local vasoconstriction induced by injected adrenalin, therefore accelerating the systemic bioavailability and potentiates the activity of adrenalin.
  • short time is meant the time of action of the antidepressant which is the time it takes for the antidepressant to block totally or partially the local vasoconstriction induced by injected adrenalin, therefore accelerating the systemic bioavailability and potentiating the activity of adrenalin.
  • the present invention also encompasses the combination of these separate aqueous solutions for use for the treatment of shocks for simultaneous administration.
  • the combination of these separate aqueous solutions is used for the treatment of anaphylactic shock for simultaneous administration.
  • the invention also relates to an auto-injection device comprising two containers wherein the pharmaceutical composition of the invention is prepared from an aqueous solution of adrenalin and an aqueous solution of an antidepressant, one container being prefilled with the aqueous solution of adrenalin, the other one container being prefilled with the aqueous solution of the antidepressant.
  • the containers are preferably prefilled syringes.
  • the invention also relates to a method of treatment of the anaphylactic shock comprising the administration of a pharmaceutical composition as defined above in a patient in need thereof.
  • Figure 1 shows the bioavailability of adrenalin when the combination according to the invention is injected in rabbits compared with adrenalin injected alone during the 10 minutes following the injection.
  • a first narrow peak in plasma adrenalin level occurred a few minutes following the injection and immediately decreased to basal level.
  • a second much larger peak of similar height occurred 20 min later.
  • the area under the curve (AUC) of this second peak was about 20 times higher than the first one indicating that the bulk of the injected dose reached the general circulation in a delayed manner, during this second period.
  • the AUC of plasma adrenalin calculated on the first 10 min following the intramuscular injection, was increased by more than 500 % whereas the total AUC remained unchanged when compared to AUCs obtained after the injection of adrenalin alone (see Fig. 1 )
  • Example 2 Synergy of the combination of adrenalin with an antidepressant in guinea pigs

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Cardiology (AREA)
  • Emergency Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Immunology (AREA)
  • Dermatology (AREA)
  • Pulmonology (AREA)
  • Hospice & Palliative Care (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Infusion, Injection, And Reservoir Apparatuses (AREA)
EP13771500.9A 2012-10-03 2013-10-02 A combination of adrenalin with an antidepressant for use in the treatment of shocks Active EP2903607B1 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
RS20170973A RS56392B1 (sr) 2012-10-03 2013-10-02 Kombinacija adrenalina sa antidepresivom za upotrebu u lečenju šokova
NO13771500A NO2903607T3 (enExample) 2012-10-03 2013-10-02
HRP20171442TT HRP20171442T1 (hr) 2012-10-03 2013-10-02 Kombinacija adrenalina s antidepresivom za uporabu u liječenju šokova
EP13771500.9A EP2903607B1 (en) 2012-10-03 2013-10-02 A combination of adrenalin with an antidepressant for use in the treatment of shocks
SM20170502T SMT201700502T1 (it) 2012-10-03 2013-10-02 Combinazione di adrenalina con un antidepressivo per l'uso nel trattamento degli shock
PL13771500T PL2903607T3 (pl) 2012-10-03 2013-10-02 Kombinacja adrenaliny z lekiem przeciwdepresyjnym do zastosowania w leczeniu wstrząsów
SI201330817T SI2903607T1 (sl) 2012-10-03 2013-10-02 Kombinacija adrenalina z antidepresivom za uporabo pri zdravljenju šokov
CY20171101135T CY1119514T1 (el) 2012-10-03 2017-10-31 Ενας συνδυασμος αδρεναλινης με ενα αντικαταθλιπτικο για χρηση στην αντιμετωπιση σοκ

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP12306207 2012-10-03
EP13771500.9A EP2903607B1 (en) 2012-10-03 2013-10-02 A combination of adrenalin with an antidepressant for use in the treatment of shocks
PCT/EP2013/070598 WO2014053579A1 (en) 2012-10-03 2013-10-02 A combination of adrenalin with an antidepressant for use in the treatment of shocks

Publications (2)

Publication Number Publication Date
EP2903607A1 EP2903607A1 (en) 2015-08-12
EP2903607B1 true EP2903607B1 (en) 2017-08-16

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EP13771500.9A Active EP2903607B1 (en) 2012-10-03 2013-10-02 A combination of adrenalin with an antidepressant for use in the treatment of shocks

Country Status (31)

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US (2) US20150306065A1 (enExample)
EP (1) EP2903607B1 (enExample)
JP (1) JP6419074B2 (enExample)
KR (1) KR102145786B1 (enExample)
CN (1) CN104780916B (enExample)
AU (1) AU2013326470B2 (enExample)
BR (1) BR112015007524B1 (enExample)
CA (1) CA2887330C (enExample)
CY (1) CY1119514T1 (enExample)
DK (1) DK2903607T3 (enExample)
EA (1) EA030763B1 (enExample)
ES (1) ES2647597T3 (enExample)
HR (1) HRP20171442T1 (enExample)
HU (1) HUE034638T2 (enExample)
IL (1) IL238120B (enExample)
IN (1) IN2015DN02849A (enExample)
LT (1) LT2903607T (enExample)
MA (1) MA37970B2 (enExample)
MX (1) MX359198B (enExample)
NO (1) NO2903607T3 (enExample)
NZ (1) NZ707124A (enExample)
PH (1) PH12015500755B1 (enExample)
PL (1) PL2903607T3 (enExample)
PT (1) PT2903607T (enExample)
RS (1) RS56392B1 (enExample)
SG (1) SG11201502645VA (enExample)
SI (1) SI2903607T1 (enExample)
SM (1) SMT201700502T1 (enExample)
TN (1) TN2015000126A1 (enExample)
WO (1) WO2014053579A1 (enExample)
ZA (1) ZA201502441B (enExample)

Family Cites Families (7)

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Publication number Priority date Publication date Assignee Title
US3705942A (en) * 1969-09-29 1972-12-12 Ciba Geigy Corp Treatment of glaucoma employing imipramine or desmethylimipramine
TW200744568A (en) * 2006-02-28 2007-12-16 Verus Pharmaceuticals Inc Epinephrine dosing regimens
US20070293582A1 (en) * 2006-06-05 2007-12-20 Malcolm Hill Epinephrine dosing regimens comprising buccal, lingual or sublingual and injectable dosage forms
EP2818184B1 (en) * 2007-11-16 2018-10-31 Allergan, Inc. Compositions and methods for treating Purpura
SE533552C2 (sv) * 2008-12-30 2010-10-26 Igeloesa Transplantation Science Ab Förfarande och lösning för behandling av en potentiell organdonator
US20100190860A1 (en) * 2009-01-09 2010-07-29 The Brigham And Women's Hospital, Inc. Methods for selectively enhancing antinociceptive potency of local anesthetics
CN101987198B (zh) * 2009-08-06 2014-08-13 北京美倍他药物研究有限公司 药物组合物

Non-Patent Citations (1)

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Also Published As

Publication number Publication date
JP6419074B2 (ja) 2018-11-07
IL238120B (en) 2018-08-30
LT2903607T (lt) 2017-10-25
MA20150396A1 (fr) 2015-11-30
ES2647597T3 (es) 2017-12-22
ZA201502441B (en) 2015-12-23
BR112015007524A2 (pt) 2017-07-04
CA2887330C (en) 2021-03-09
BR112015007524B1 (pt) 2022-06-21
MA37970B2 (fr) 2017-10-31
PH12015500755A1 (en) 2015-05-25
MX359198B (es) 2018-09-19
TN2015000126A1 (en) 2016-10-03
WO2014053579A1 (en) 2014-04-10
SI2903607T1 (sl) 2017-12-29
PT2903607T (pt) 2017-11-14
IN2015DN02849A (enExample) 2015-09-11
JP2015536907A (ja) 2015-12-24
SMT201700502T1 (it) 2017-11-15
CA2887330A1 (en) 2014-04-10
RS56392B1 (sr) 2017-12-29
AU2013326470A1 (en) 2015-04-30
CN104780916A (zh) 2015-07-15
KR20150093656A (ko) 2015-08-18
CY1119514T1 (el) 2018-03-07
EA030763B1 (ru) 2018-09-28
MA37970B1 (fr) 2016-06-30
HRP20171442T1 (hr) 2018-01-12
EP2903607A1 (en) 2015-08-12
NZ707124A (en) 2017-12-22
US20190117614A1 (en) 2019-04-25
AU2013326470B2 (en) 2017-08-24
US10952987B2 (en) 2021-03-23
PL2903607T3 (pl) 2018-01-31
KR102145786B1 (ko) 2020-08-19
CN104780916B (zh) 2019-02-26
DK2903607T3 (en) 2017-10-09
EA201500374A1 (ru) 2015-07-30
NO2903607T3 (enExample) 2018-01-13
HK1211846A1 (en) 2016-06-03
PH12015500755B1 (en) 2015-05-25
US20150306065A1 (en) 2015-10-29
MX2015004323A (es) 2015-06-10
HUE034638T2 (en) 2018-02-28
SG11201502645VA (en) 2015-05-28

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